Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gemcitabine (dFdC) and DMDC are new antimetabolites with good antitumor activities against various tumors which include human leukemic cell lines and a number of rodent and human solid tumors and human tumor. They are structurally related to cytarabine (Ara-C) which is known as one of the most effective drugs against adult acute leukemia, but many solid tumors are insensitive not been found to the drug. Gemcitabine acts as an inhibitor of ribonucleoside diphosphate reductase and inhibits DNA synthesis. Biochemically Gemcitabine is rapidly phosphorylated to dFdCTP which has a comparatively longer half-life than that of Ara-C, showing a therapeutic activity against tumors. In the phase I trials, the reported maximum-tolerated doses were 790 mg/m2 to 1370 mg/m2 at the schedule of 30 minutes i.v. infusion once a week for three weeks but higher dose levels (2,500 mg/m2 to 4,800 mg/m2) were reported in the schedule of prolongation of the infusion time. Reported toxicities were myelosuppression, fatigability, fever, appetite loss and skin rash. Toxicities were seemed to be mild. In USA, Europe and South Africa, phase II trials of Gemcitabine at the schedule of 30 minutes infusion once a week for three weeks followed by one week rest were performed against solid tumors (breast cancer, ovarian cancer, renal cancer, colorectal cancer, pancreas cancer, head and neck cancer, and lung cancer) and showed good responses to those tumors. DMDC was developed in Japan, and a phase I trial is currently on-going.
 ...
PMID:[New antitumor antimetabolites--gemcitabine and DMDC]. 133 22

The pyrimidine antimetabolite gemcitabine is an analogue of cytosine arabinosid. Gemcitabine is well tolerated when given in doses of 1000-1250 mg/m2 weekly x 3 followed by 1 weeks rest, with mild myelosuppression as the major toxicity. In five studies, including a total of 250 patients with previously untreated non-small cell lung cancer (NSCLC), response rates from 20 to 28% were observed, ranking gemcitabine among the active agents in NSCLC. Gemcitabine should be further explored in combination therapy for NSCLC.
Lung Cancer 1995 Apr
PMID:Gemcitabine in non-small cell lung cancer. 755 26

2',2'-Difluorodeoxycytidine (Gemcitabine, dFdC) is a relatively new deoxycytidine antimetabolite, with established activity against ovarian cancer and non-small-cell lung cancer. dFdC is assumed to exert its antitumour effect mainly by incorporation of the triphosphate dFdCTP into DNA. We determined the sensitivity to dFdC of six cell lines derived from solid tumours; two ovarian carcinoma (A2780 and OVCAR-3), two colon carcinoma (WiDr and C26-10) and two squamous cell carcinoma cell lines (UM-SCC-14C and UM-SCC-22B). In vitro sensitivity to dFdC was strongly time dependent. Under all conditions A2780 was the most sensitive cell line with an IC50 (the concentration of dFdC causing 50% growth inhibition) of 31 and 0.6 nM at 1 and 48 hr exposure, respectively. WiDr and C26-10 cells were relatively insensitive, with IC50s of 468 and 1133 nM, respectively, at 1 hr exposure, but of 11 and 6 nM at 48 hr exposure. Accumulation of the triphosphate dFdCTP was also time dependent. After 4 hr exposure to 10 microM dFdC, A2780, WiDr and C26-10 cells accumulated 223, 136 and 267 pmol/10(6) cells, respectively; after 24 hr exposure they accumulated 1045, 619 and 617 pmol/10(6) cells, respectively. A2780 cells retained the high dFdCTP concentration longer than 24 hr. For comparison purposes we also studied dFdCTP kinetics in the corresponding solid tumours, showing the same sensitivity pattern as the cell lines. In general, sensitivity to dFdC in vitro related with dFdCTP accumulation and retention, but in vivo this relation was less clear. Unexpectedly, remarkable in vitro and in vivo changes were observed in the ribonucleotide pools. The most predominant in vitro cell line dependent changes were a decrease in CTP concentrations, accompanied by an increase in UTP and GTP concentrations. In vivo CTP, UTP and GTP pools increased in all tumours. In conclusion, in this study we demonstrate that dFdCTP is accumulated and retained in solid tumours and cell lines. dFdCTP is not only important as a DNA precursor, but also appears to interfere with normal ribonucleotide metabolism.
 ...
PMID:Schedule dependence of sensitivity to 2',2'-difluorodeoxycytidine (Gemcitabine) in relation to accumulation and retention of its triphosphate in solid tumour cell lines and solid tumours. 794 30

Gemcitabine is a new ara-C derivative and shows much more potent cytotoxic action than ara-C, which may be explained by the fact that its intracellular concentration can be maintained over a longer period. We investigated anti-tumor activity combining gemcitabine with cisplatin (CDDP) or vindesine (VDS) with a lung cancer line H-74 that was relatively insensitive to gemcitabine. Mice were observed for 8 weeks, including the 4 week treatment period and the subsequent 4 week drug-free period. The tumor growth inhibition rate, histological changes, and side effects were evaluated at 4 and 8 weeks after the initiation of therapy. The anti-tumor effects of treatment combining gemcitabine with CDDP or VDS were more potent and lasted longer than each drug separately. Statistical analysis shows that the treatment combining gemcitabine with CDDP was additive or synergistic at 4 and 8 weeks after initiation, whereas the treatment combining gemcitabine with VDS was only additive at 4 weeks after initiation and additive or synergistic at 8 weeks after initiation. The side effects of both combination groups were less than those observed in only CDDP or VDS-treated animals. These results suggest the usefulness of a combination therapy combining gemcitabine with CDDP or VDS in future clinical applications.
 ...
PMID:[Antitumor activity of combination treatment combining gemcitabine with cisplatin or vindesine against human lung cancer xenografted in nude mice]. 797 19

Two analogues of cytosine arabinoside (ara-C) and three analogues of methotrexate (MTX) are under their clinical studies in Japan. Gemcitabine and DMDC are analogues of ara-C, showing similar antitumor efficacies each other and rather mild animal toxicities. Currently, dFdC is under phase II study, showing activity against lung cancer and DMDC under phase I study. As for MTX analogues, edatrexate, trimetrexate and TNP-351 have been put on the clinical phase studies. Among these antifolates, both edatrexate and trimetrexate have showed responses against lung cancer and we expect that TNP-351 may also show a similar response in the future. Currently, phase II studies of edatrexate and trimetrexate and phase I study of TNP-351 are under progress.
 ...
PMID:[Development of antimetabolites, II]. 842 84

Gemcitabine is a nucleoside analogue with activity in non-small-cell lung cancer (NSCLC). Phase I trials have determined the best tolerated dose of gemcitabine in chemotherapy-naive patients to be 1250 mg/m2 given as a 30-minute infusion weekly x 3 every 4 weeks. The single-agent efficacy of gemcitabine has been assessed in 4 phase II trials (361 patients) at dose of 800-1250 mg/m2/weekly x 3 every 4 weeks. Single-agent response rates (externally verified by Oncology Review Board) were > 20%, with duration of response 7.6-12.7 months and median survival 8-9 months. Dose-limiting toxicity was neutropenia, but this was rare, even at the highest dose levels. In 3 Japanese studies, response rates of 16.3%, 26% and 20.9% were seen in untreated patients. Pooled data from all NSCLC studies shows that responses were seen in stages IIIA, IIIB and IV disease, and were similar in adeno and squamous cell types. Gemcitabine has also been studied in combination with other drugs active in NSCLC. In one study 50 patients were treated with gemcitabine and cisplatin given weekly x 3 every 4 weeks, cisplatin at a dosage of 25-30 mg/m2 and gemcitabine at doses escalating from 1000 mg/m2 in steps of 250 mg/m2 per cycle, 38 of 50 patients have been evaluated to date, with an overall response rate of 31.6%. Dose limiting toxicity was rare, but there was evidence of cumulative haematological toxicity with grade 4 granulocytopenia and thrombocytopenia becoming more frequent with repeated administration. Similar activity was seen when gemcitabine (1000 mg/m2) was combined with monthly cisplatin (60, 75, 100 mg/m2). Other studies have shown that gemcitabine can enhance radiosensitivity in NSCLC and other solid tumour types such as pancreas/breast and colorectal cancer cell lines.
 ...
PMID:Gemcitabine in the treatment of non-small-cell lung cancer. 861 18

A phase I study to determine the maximum tolerated dose and toxicity of gemcitabine when given as a 24 h infusion to patients with inoperable non-small-cell lung cancer (NSCLC). A total of 24 patients with unresectable stage IIIa-IV NSCLC were entered into the study. Gemcitabine was administered as a 24 h infusion on days 0, 7 and 14. Courses of therapy were repeated every 28 days. There were 16 males and 8 females with a median age of 51 years (range 40-73 years). The WHO performance score was 1 (21 patients) or 2 (3 patients). The TNM stage was IIIa (6), IIIb (10) and IV (8). Three patients were entered at each dose level with six at the maximum tolerated dose (MTD). Dose levels were 10, 20, 40, 80, 120, 180 and 210 mg m-2. The MTD was 180 mg m-2 and dose-limiting toxicity was neutropenia and lethargy. Partial response was observed in five (21%) patients (95% CI 7-42%) lasting 10, 14, 18, 47 and 51 + weeks. The maximum tolerated dose of gemcitabine given as a 24 h infusion was 180 mg m-2.
 ...
PMID:A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer. 869 65

A phase I trial was performed to investigate the tolerability and efficacy of the novel nucleoside analogue gemcitabine in combination with cisplatin in the treatment of advanced non-small cell lung cancer. Both cisplatin and gemcitabine were administered as 30 min infusions weekly x 3 with a week of rest. There was one dose escalation of cisplatin from 25 mg/m2 (dose level 1) to 30 mg/m2 (in subsequent dose levels 2-5), such that the mean dose intensity for the weekly x 3 q 4 week cycle was 22.5 mg/m2/week which is close to that achieved with 100 mg/m2 bolus monthly. Gemcitabine was initiated at 1000 mg/m2 (dose levels 1 and 2) then escalated by 250 mg/m2/week to 1750 mg/m2 (dose level 5). Of 32 chemotherapy-naive patients entered (22 males, 10 females; median age 61 years, range 29-74 years), 11 had localized tumours (2 stage IIIa, 9 IIIb) and 21 had stage IV tumours with haematogenous metastases and a poor prognosis. Twenty-one patients had adenocarcinoma, 4 squamous cell carcinoma, 6 large cell undifferentiated tumors, and one had mixed squamous and adenocarcinoma. Dose-limiting toxicity was not seen in more than one patient in cycle 1 at any dose level. Grade 4 granulocytopenia and thrombocytopenia occurred more frequently with repeated dosing, necessitating dose reductions except at the lowest dose level (cisplatin 25 mg/m2, gemcitabine 1000 mg/m2). Non-haematological toxicity was mild and rapidly reversible. Cisplatin administration led to a higher frequency of nausea and vomiting than that seen with gemcitabine alone, but this was easily controlled with antiemetics. In the 28 patients evaluable, to date responses have been seen at most dose levels, with an overall response rate 35.7%. This phase I trial is ongoing and further dose escalation is intended to determine the MTD of gemcitabine.
Lung Cancer 1996 Feb
PMID:Phase I trial of gemcitabine and cisplatin in advanced non-small cell lung cancer: a preliminary report. 869 17

Although chemotherapy costs have not been highlighted traditionally, there is increasing pressure to demonstrate the value of new treatments within the health care budget. Pharmaceutical companies are assessing the economic value of their products before launch. Gemcitabine is a nucleoside analogue developed for use in solid tumours. The purpose of this model was to investigate the clinical outcomes and potential cost savings for gemcitabine used as monotherapy compared to cisplatin and etoposide combination therapy in late stage non-small cell lung cancer (NSCLC), in a palliative (as opposed to aggressive) chemotherapy setting. Gemcitabine treatment data were taken from a large NSCLC study and data from retrospective chart reviews identified through the National Oncology Data Base. The model population and effectiveness of the two regimens were judged to be similar, except for baseline performance status. If drug costs were not included, the probability distribution resulting from the simulation showed median cost savings per cycle ranging from $US 1504 to $US 7425, with a medium value of $US 2154. The model suggested that gemcitabine would result in cost savings per cycle more than 90% of the time. Outpatient versus inpatient drug administrations accounted for the majority of potential cost savings. Most of the remaining cost savings were attributable to the difference in febrile neutropenia and antiemetic use. This economic model showed susbstantial savings if gemcitabine was used instead of cisplatin and etoposide combination therapy in the United States' community care setting. Some savings would be realized even if the location of treatment for both regimens was mostly outpatient. Assessment of the product's economic value before launch has assisted in our understanding of the potential areas of cost savings for gemcitabine and has guided us in the design of prospective randomized studies which included pharmacoeconomic endpoints.
Lung Cancer 1996 Feb
PMID:Economic value of gemcitabine compared to cisplatin and etoposide in non-small cell lung cancer. 869 16

Statistics Canada (Ottawa, Canada) is developing a population health model (POHEM) that simulates the health and common illnesses of Canadians. The POHEM incorporates a model of lung cancer management based on Canadian practice, which has been used to estimate the total direct care costs of treating all lung cancer cases diagnosed in Canada in 1988. One of the potential uses of the POHEM is to evaluate the cost and cost effectiveness of new therapeutic interventions as they are introduced into practice. Gemcitabine, a new nucleoside analog with a broad spectrum of antitumor activity, has been evaluated in the model and estimates have been made of its cost effectiveness in the management of lung cancer over a range of drug costs per treatment cycle ($Cdn 800 to $Cdn 1,800). The survival of stage IV non-small cell lung cancer (NSCLC) patients treated on an international trial of gemcitabine (E018) was used to estimate the potential survival gain relative to the survival of stage IV NSCLC patients managed with best supportive care on a randomized trial conducted by the National Cancer Institute of Canada. Sensitivity analyses were performed assuming that the survival benefit was 25% and 50% less than that reported in the E018 trial. Based on the apparent survival advantage of the E018 trial, the cost per life-year gained ranged from $Cdn 1,609 to $Cdn 9,529 depending on the cost per treatment cycle. At the greatest cost per cycle ($Cdn 1,800) and with survival reduced by 50% as compared with the E018 result, the cost per life-year gained was estimated to be $Cdn 16,230. From these estimates of direct care costs in the Canadian health care system, gemcitabine appears to be a cost-effective intervention for advanced NSCLC.
 ...
PMID:An estimate of the cost effectiveness of gemcitabine in stage IV non-small cell lung cancer. 889 88


1 2 3 4 5 6 7 8 9 10 Next >>